U.S. patent application number 10/025426 was filed with the patent office on 2002-09-05 for carboxylic acid amides, pharmaceutical compositions containing these compounds, their use and the preparation thereof.
Invention is credited to Damm, Klaus, Hauel, Norbert, Priepke, Henning, Schnapp, Andreas.
Application Number | 20020123509 10/025426 |
Document ID | / |
Family ID | 7669003 |
Filed Date | 2002-09-05 |
United States Patent
Application |
20020123509 |
Kind Code |
A1 |
Hauel, Norbert ; et
al. |
September 5, 2002 |
Carboxylic acid amides, pharmaceutical compositions containing
these compounds, their use and the preparation thereof
Abstract
The present application relates to new carboxylic acid amides of
general formula 1 wherein A, B and R.sub.1 to R.sub.3 are defined
as in claim 1, processes for preparing them, pharmaceutical
compositions containing these compounds and the use thereof and
their preparation.
Inventors: |
Hauel, Norbert;
(Schemmerhofen, DE) ; Priepke, Henning;
(Warthausen, DE) ; Damm, Klaus; (Biberach, DE)
; Schnapp, Andreas; (Biberach, DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Family ID: |
7669003 |
Appl. No.: |
10/025426 |
Filed: |
December 19, 2001 |
Current U.S.
Class: |
514/311 ;
514/357; 514/456; 546/176; 546/336; 549/396 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 215/14 20130101; C07D 333/54 20130101 |
Class at
Publication: |
514/311 ;
514/357; 514/456; 549/396; 546/176; 546/336 |
International
Class: |
A61K 031/47; A61K
031/44; A61K 031/353; C07D 311/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 2000 |
DE |
100 65 043.0 |
Claims
What is claimed is:
1. A carboxylic acid amide of formula I 6wherein R.sub.1 is a
hydrogen atom or a C.sub.1-3-alkyl group, R.sub.2 is a hydrogen,
fluorine, chlorine or bromine atom or a C.sub.1-3-alkyl group,
R.sub.3 is a hydrogen atom or a C.sub.1-5-alkyl group, A is a
chromane or chromene group linked via a fused-on phenyl ring
wherein a methylene group may be replaced by a carbonyl group, or a
bicyclic heteroaryl group consisting of a 5- or 6-membered
heteroaryl group optionally substituted in the carbon skeleton by a
fluorine, chlorine or bromine atom or by a C.sub.1-3-alkyl or
C.sub.1-3-alkoxy group, wherein the 6-membered heteroaryl groups
contain one, two or three nitrogen atoms and the 5-membered
heteroaryl groups contain an imino group optionally substituted by
a C.sub.1-3-alkyl group, an oxygen or sulphur atom, or an imino
group optionally substituted by a C.sub.1-3-alkyl group and an
oxygen or sulphur atom or one or two nitrogen atoms, and a phenyl
ring fused to the abovementioned monocyclic heteroaryl groups via
two adjacent carbon atoms, by means of which the bicyclic
heteroaryl group is linked to the R.sub.1-substituted alkene-carbon
atom and which may also be substituted in the carbon skeleton by a
fluorine, chlorine or bromine atom or by a C.sub.1-3-alkyl or
C.sub.1-3-alkoxy group, and B is a 5- or 6-membered heteroaryl
group substituted by a carboxy group or by a group which may be
converted into a carboxy group in vivo or a phenyl or naphthyl
group which is substituted in each case by a carboxy group, by a
group which may be converted into a carboxy group in vivo or by a
group which is negatively charged under physiological conditions,
while the abovementioned phenyl group may additionally be
substituted by a fluorine, chlorine, bromine or iodine atom, by a
C.sub.1-3-alkyl, trifluoromethyl, phenyl, hydroxy,
C.sub.1-3-alkoxy, C.sub.1-3-alkyl-sulphonyloxy, phenylsulphonyloxy,
carboxy, C.sub.1-3-alkoxycarbonyl, formyl, C.sub.1-3-alkylcarbonyl,
C.sub.1-3-alkylsulphonyl, phenylsulphonyl, nitro, pyrrolidino,
piperidino, morpholino, N-(C.sub.1-3-alkyl)-piperazino,
aminosulphonyl, C.sub.1-3-alkylaminosulphonyl- or
di-(C.sub.1-3-alkyl)-aminosulphonyl group, by an n-C.sub.2-3-alkoxy
group substituted in the 2 or 3 position by a
di-(C.sub.1-3-alkyl)-amino group, by an amino group, by an
N-(C.sub.1-3-alkyl)-amino or N,N-di-(C.sub.1-3-alkyl)-amino group
wherein the alkyl moiety in the 2 or 3 position relative to the
nitrogen atom may be substituted in each case by a C.sub.1-3-alkoxy
group, by an N-phenylamino, N-(phenyl-C.sub.1-3-alkyl)-amino or
N-(pyridyl-C.sub.1-3-alkyl)-amino group, by an aminocarbonyl group
which may be mono- or disubstituted at the amino-nitrogen atom by a
C.sub.1-3-alkyl group, by a pyrrolidinocarbonyl,
piperidinocarbonyl, morpholinocarbonyl or
N-(C.sub.1-3-alkyl)-piperazinocarbonyl group, by a sulphonyl group
substituted by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, pyrrolidino, piperidino, morpholino or
N-(C.sub.1-3-alkyl)-piperazino group, by an amino or
N-(C.sub.1-3-alkyl)-amino group which is substituted in each case
at the amino-nitrogen atom by an aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, phenyl-C.sub.1-3-alkylaminocarbonyl,
phenylaminocarbonyl, pyridylaminocarbonyl, pyrrolidinocarbonyl,
piperidinocarbonyl, morpholinocarbonyl or
N-(C.sub.1-3-alkyl)-piperazinocarbonyl group, whilst in the
abovementioned aminocarbonyl groups any hydrogen atom present may
additionally be replaced by a C.sub.1-3-alkyl group, or by a 5 or
6-membered heteroaryl group, whilst the abovementioned phenyl
groups may additionally be substituted by another fluorine,
chlorine or bromine atom or by another C.sub.1-3-alkyl or
C.sub.1-3-alkoxy group and two C.sub.1-3-alkoxy groups in the o
position may be replaced by a methylenedioxy group, and the
abovementioned 6-membered heteroaryl groups contain one, two or
three nitrogen atoms and the abovementioned 5-membered heteroaryl
groups contain an imino group optionally substituted by a
C.sub.1-3-alkyl group, an oxygen or sulphur atom, or an imino group
optionally substituted by a C.sub.1-3-alkyl group and an oxygen or
sulphur atom or one or two nitrogen atoms, an isomer thereof or a
salt thereof.
2. The carboxylic acid amide according to claim 1, wherein R.sub.1
is a hydrogen atom or a C.sub.1-3-alkyl group, R.sub.2 is a
hydrogen, fluorine, chlorine or bromine atom or a C.sub.1-3-alkyl
group, R.sub.3 is a hydrogen atom or a methyl group, A is a
chromane or chromene group linked via a fused-on phenyl ring
wherein a methylene group may be replaced by a carbonyl group, or a
bicyclic heteroaryl group consisting of a 5 or 6-membered
heteroaryl group optionally substituted in the carbon skeleton by a
fluorine, chlorine or bromine atom, by a C.sub.1-3-alkyl or
C.sub.1-3-alkoxy group, while the 6-membered heteroaryl groups
contain one, two or three nitrogen atoms and the 5-membered
heteroaryl groups contain an imino group optionally substituted by
a C.sub.1-3-alkyl group, an oxygen or sulphur atom, or an imino
group optionally substituted by a C.sub.1-3-alkyl group and an
oxygen or sulphur atom or one or two nitrogen atoms, and a phenyl
ring fused to the abovementioned monocyclic heteroaryl groups via
two adjacent carbon atoms, by means of which the bicyclic
heteroaryl group is linked to the R.sub.1 -substituted
alkene-carbon atom and which may also be substituted in the carbon
skeleton by a fluorine, chlorine or bromine atom or by a methyl or
methoxy group, and B is a 5 or 6-membered heteroaryl group
substituted by a carboxy group or by a group which may be converted
into a carboxy group in vivo or a phenyl or naphthyl group which is
substituted in each case by a carboxy group or by a group which may
be converted into a carboxy group in vivo, while the abovementioned
phenyl group is additionally substituted by a fluorine, chlorine or
bromine atom, by a C.sub.1-3-alkyl, trifluoromethyl, phenyl,
hydroxy, C.sub.1-3-alkoxy, carboxy, C.sub.1-3-alkoxycarbonyl,
formyl, C.sub.1-3-alkylcarbonyl, C.sub.1-3-alkylsulphonyl,
phenylsulphonyl, nitro, pyrrolidino, piperidino, morpholino,
N-(C.sub.1-3-alkyl)-piperazin- o, aminosulphonyl,
C.sub.1-3-alkylaminosulphonyl or
di-(C.sub.1-3-alkyl)-aminosulphonyl group, by a
n-C.sub.2-.sub.3-alkoxy group substituted in the 2 or 3 position by
a di-(C.sub.1-3-alkyl)-amino group, by an amino group, by an
N-(C.sub.1-3-alkyl)-amino or N,N-di-(C.sub.1-3-alkyl)-amino group
wherein the alkyl moiety in the 2 or 3 position relative to the
nitrogen atom may be substituted in each case by a C.sub.1-3-alkoxy
group, by an N-phenylamino, N-(phenyl-C.sub.1-3-alk- yl)-amino or
N-(pyridyl-C.sub.1-3-alkyl)-amino group, by an aminocarbonyl group
which may be mono or disubstituted at the amino-nitrogen atom by a
C.sub.1-3-alkyl group, by a pyrrolidinocarbonyl,
piperidinocarbonyl, morpholinocarbonyl or
N-(C.sub.1-3-alkyl)-piperazinocarbonyl group, by a sulphonyl group
substituted by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, pyrrolidino, piperidino, morpholino or
N-(C.sub.1-3-alkyl)-piperazino group, or by an amino or
N-(C.sub.1-3-alkyl)-amino group which is substituted in each case
at the amino-nitrogen atom by an aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, phenyl-C.sub.1-3-alkylaminocarbonyl,
phenylaminocarbonyl, pyridylaminocarbonyl, pyrrolidinocarbonyl,
piperidinocarbonyl, morpholinocarbonyl or
N-(C.sub.1-3-alkyl)-piperazinocarbonyl group, wherein additionally
any hydrogen atom present in one of the abovementioned
aminocarbonyl groups may be replaced by a C.sub.1-3-alkyl group,
whilst the abovementioned phenyl groups may additionally be
substituted by another fluorine, chlorine or bromine atom or by
another C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, and the
abovementioned 6-membered heteroaryl groups contain one or two
nitrogen atoms and the abovementioned 5-membered heteroaryl groups
contain an imino group optionally substituted by a C.sub.1-3-alkyl
group, an oxygen or sulphur atom, or an imino group optionally
substituted by a C.sub.1-3-alkyl group and an oxygen or sulphur
atom or one or two nitrogen atoms, an isomer thereof or a salt
thereof.
3. The carboxylic acid amide according to claim 2, wherein A is a
chromane or chromene group linked via the fused-on phenyl ring,
wherein a methylene group may be replaced by a carbonyl group, or a
bicyclic heteroaryl group consisting of a 5 or 6-membered
heteroaryl group optionally substituted in the carbon skeleton by a
fluorine, chlorine or bromine atom, by a methyl or methoxy group,
while the 6-membered heteroaryl groups contain one, two or three
nitrogen atoms and the 5-membered heteroaryl groups contain an
imino group optionally substituted by a methyl group, an oxygen or
sulphur atom, or an imino group optionally substituted by a methyl
group and an oxygen or sulphur atom or one or two nitrogen atoms,
and a phenyl ring fused to the abovementioned monocyclic heteroaryl
groups via two adjacent carbon atoms, by means of which the
bicyclic heteroaryl group is linked to the R.sub.1 substituted
alkene-carbon atom and which may also be substituted in the carbon
skeleton by a fluorine, chlorine or bromine atom or by a methyl or
methoxy group, an isomer thereof or a salt thereof.
4. The carboxylic acid amide according to claim 1, wherein R.sub.1
is a hydrogen atom or a C.sub.1-3-alkyl group, R.sub.2 is a
hydrogen atom or a methyl group, R.sub.3 is a hydrogen atom, A is a
benzofuryl, benzothienyl, quinolyl or isoquinolyl group bound via
the phenyl moiety to the R.sub.1-substituted alkene-carbon atom and
optionally substituted by a methyl group and B is a pyridyl,
thienyl, pyrazolyl, quinolyl or isoquinolyl group substituted by a
carboxy group or a phenyl group substituted by a carboxy,
methoxycarbonyl or ethoxycarbonyl group, which may additionally be
substituted by a fluorine, chlorine or bromine atom, by a methyl,
trifluoromethyl, phenyl, hydroxymethyl, hydroxy, methoxy,
2-dimethylamino-ethoxy, nitro, methylsulphonylamino,
phenylsulphonylamino, aminosulphonyl, pyrrolidino, piperidino or
morpholino group, by an amino, N-methyl-amino or
N-(2-methoxy-ethyl)-amin- o group which may be substituted in each
case at the amino-nitrogen atom by a C.sub.1-3-alkyl group, or by
an aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl
group, whilst the abovementioned phenyl groups may additionally be
substituted by another fluorine or chlorine atom or by another
methyl or methoxy group, an isomer thereof or a salt thereof.
5. The carboxylic acid amide according to claim 1, wherein R.sub.1
is a hydrogen atom, a methyl or ethyl group, R.sub.2 is a hydrogen
atom, R.sub.3 is a hydrogen atom, A is a benzothienyl, quinolyl or
isoquinolyl group bound to the R.sub.1 -substituted alkene-carbon
atom via the phenyl moiety and optionally substituted by a methyl
group and B is a phenyl, thienyl or pyridinyl group substituted in
each case by a carboxy group, while the abovementioned phenyl group
may additionally be substituted by a fluorine, chlorine or bromine
atom, by a methyl, hydroxy, C.sub.1-3-alkoxy, pyrrolidino,
piperidino, morpholino or N-(C.sub.1-3-alkyl)-piperazino group, by
a 2-dimethylaminoethoxy group, by an amino, methylamino or
dimethylamino group or by an aminocarbonyl, methylaminocarbonyl or
dimethylaminocarbonyl group and the disubstituted phenyl groups may
additionally be substituted by another fluorine atom or by another
methyl or methoxy group, an isomer thereof or a salt thereof.
6. The carboxylic acid amide according to claim 1, wherein R.sub.1
is a methyl group, R.sub.2 is a hydrogen atom, R.sub.3 is a
hydrogen atom, A is a benzothienyl, quinolyl or isoquinolyl group
bound to the R.sub.1 -substituted alkene-carbon atom via the phenyl
moiety and B is a 2-carboxy-phenyl or 2-carboxy-thienyl group,
while the abovementioned 2-carboxy-phenyl group may additionally be
substituted in the phenyl nucleus by a fluorine, chlorine or
bromine atom, by a methyl, hydroxy, C.sub.1-3-alkoxy, amino,
methylamino, dimethylamino or morpholino group, by a
2-dimethylaminoethoxy group or by an aminocarbonyl,
methylaminocarbonyl or dimethylaminocarbonyl group and optionally
additionally by another fluorine atom or by another methoxy group,
an isomer thereof or a salt thereof.
7. The carboxylic amide according to claim 1: (1)
trans-3-(benzothien-6-yl- )-but-2-enoic
acid-N-(2-carboxy-phenyl)-amide, (2) trans-3-(benzothien-5-y-
l)-but-2-enoic acid-N-(2-carboxy-phenyl)-amide, (3)
trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-4,5-dimethoxyphen- yl)-amide, (4)
trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-6-methylphenyl)-amide, (5)
trans-3-(benzothien-6-yl)-bu- t-2-enoic
acid-N-(2-carboxy-4-fluorophenyl)-amide; or (6)
trans-3-(quinolin-6-yl)-but-2-enoic
acid-N-(2-carboxy-phenyl)-amide; or a salt thereof.
8. The physiologically acceptable salt of the carboxylic amide
according to claim 1.
9. A pharmaceutical composition comprising a carboxylic amide
according to claim 1 together with one or more inert carriers or
diluents.
10. A method for treating disease in a warm-blooded animal, which
disease involves an excess production of telomerase which comprises
administering to the animal a therepeutically effective dose of a
carboxylic amide according to claim 1.
Description
[0001] The last decade of oncological research has made it possible
for the first time to achieve a molecular understanding of the
regulatory mechanisms involved in the formation of tumours. These
include, for example, the function of oncogenes, tumour suppressor
genes, growth factors, receptors, signal transduction cascades,
pro- and anti-apoptotic genes in controlling cell growth,
differentiation, migration and cell death. These new findings have
also shown, however, that cancer is a multifactorial disease at the
molecular level, during the onset of which tissues may undergo
malignant degeneration as a result of different mechanisms. This
heterogeneity of the malignant cells in turn explains the clinical
problems of tumour therapy.
[0002] As long ago as 1965 Hayflick postulated (Hayflick, Exp. Cell
Res. 37, 614-636 (1965)) that the limited proliferative lifespan of
normal somatic cells, replicative senescence, may act as a tumour
suppressor mechanism. This hypothesis was supported by experimental
work which showed that overcoming replicative senescence is a
prerequisite for the malignant transformation of cells (Newbold et
al. in Nature, 299, 633-636 (1989); Newbold and Overell in Nature,
304, 648-651 (1983)).
[0003] However, only in the last few years has there been any
understanding of the molecular mechanisms by which somatic cells
achieve the state of replicative senescence.
[0004] The ends of eukaryotic chromosomes, the telomers, consist of
simple repetitive sequences the integrity of which is essential for
the function and structure of the chromosomes. However, linear
chromosomes lose a certain length of their telomers in each round
of DNA replication, a phenomenon which was recognised by Watson
back in 1972 (Watson in Nature New Biol. 239, 197-201 (1972)). The
cumulative loss of telomeric DNA over numerous cell divisions
constitutes the reason for the limited replicative potential of
somatic cells, whereas more than 85% of all tumours in humans
reactivate an enzyme, telomerase, to compensate for the loss of
telomers and thus become immortal (see Shay and Bacchetti in
European Journal of Cancer, 33, 787-791 (1997)).
[0005] Telomerase in humans is a ribonucleoprotein (RNP) which is
made up of at least one catalytic subunit (hTERT), and one RNA
(hTR). Both components have been molecularly cloned and
characterised. Biochemically, telomerase is a reverse transcriptase
which uses a sequence fragment in hTR as a matrix in order to
synthesise a strand of telomeric DNA (Morin in Cell 59, 521-529
(1989)). Methods of identifying telomerase activity as well as
methods of diagnosing and treating replicative senescence and
immortality by modifying telomers and telomerase have already been
described (Morin in Cell 59, 521-529 (1989); Kim et al. in Science
266, 2011-2014 (1994)).
[0006] Inhibitors of telomerase may be used for tumour therapy, as
somatic cells, unlike tumour cells, are not dependent on
telomerase.
[0007] Moreover, U.S. Pat. No. 3,940,422 inter alia describes the
compound trans-3,4-dimethoxy-cinnamic acid-N-anthranilic
acid-amide, which has antiallergenic properties, in particular.
[0008] It has now been found that the carboxylic acid amides of
general formula 2
[0009] the isomers thereof, particularly the trans-isomers thereof,
and the salts thereof, particularly the physiologically acceptable
salts thereof, surprisingly have an inhibiting effect on
telomerase.
[0010] The present invention relates to the new carboxylic acid
amides of the above general formula I and the salts thereof,
particularly the physiologically acceptable salts thereof, which
have an inhibiting effect on telomerase, processes for preparing
them, pharmaceutical compositions containing these compounds and
the use thereof.
[0011] In the new carboxylic acid amides of the above general
formula I
[0012] R.sub.1 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0013] R.sub.2 denotes a hydrogen, fluorine, chlorine or bromine
atom or a C.sub.1-3-alkyl group,
[0014] R.sub.3 denotes a hydrogen atom or a C.sub.1-5-alkyl
group,
[0015] A denotes a chromane or chromene group linked via a fused-on
phenyl ring wherein a methylene group may be replaced by a carbonyl
group,
[0016] or a bicyclic heteroaryl group consisting of
[0017] a 5- or 6-membered heteroaryl group optionally substituted
in the carbon skeleton by a fluorine, chlorine or bromine atom or
by a C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, wherein the
6-membered heteroaryl groups contain one, two or three nitrogen
atoms and the 5-membered heteroaryl groups contain an imino group
optionally substituted by a C.sub.1-3-alkyl group, an oxygen or
sulphur atom, or an imino group optionally substituted by a
C.sub.1-3-alkyl group and an oxygen or sulphur atom or one or two
nitrogen atoms, and a phenyl ring fused to the abovementioned
monocyclic heteroaryl groups via two adjacent carbon atoms, by
means of which the bicyclic heteroaryl group is linked to the
R.sub.1 -substituted alkene-carbon atom and which may also be
substituted in the carbon skeleton by a fluorine, chlorine or
bromine atom or by a C.sub.1-3-alkyl or C.sub.1-3-alkoxy group,
[0018] and B denotes a 5- or 6-membered heteroaryl group
substituted by a carboxy group or by a group which may be converted
into a carboxy group in vivo
[0019] or a phenyl or naphthyl group which is substituted in each
case by a carboxy group, by a group which may be converted into a
carboxy group in vivo or by a group which is negatively charged
under physiological conditions, while the abovementioned phenyl
group may additionally be substituted
[0020] by a fluorine, chlorine, bromine or iodine atom,
[0021] by a C.sub.1-3-alkyl, trifluoromethyl, phenyl, hydroxy,
C.sub.1-3-alkoxy, C.sub.1-3-alkyl-sulphonyloxy, phenylsulphonyloxy,
carboxy, C.sub.1-3-alkoxycarbonyl, formyl, C.sub.1-3-alkylcarbonyl,
C.sub.1-3-alkylsulphonyl, phenylsulphonyl, nitro, pyrrolidino,
piperidino, morpholino, N-(C.sub.1-3-alkyl)-piperazino,
aminosulphonyl, C.sub.1-3-alkylaminosulphonyl- or
di-(C.sub.1-3-alkyl)-aminosulphonyl group,
[0022] by an n-C.sub.2-3-alkoxy group substituted in the 2 or 3
position by a di-(C.sub.1-3-alkyl)-amino group,
[0023] by an amino group, by an N-(C.sub.1-3-alkyl)-amino or
N,N-di-(C.sub.1-3-alkyl)-amino group wherein the alkyl moiety in
the 2 or 3 position relative to the nitrogen atom may be
substituted in each case by a C.sub.1-3-alkoxy group, by an
N-phenylamino, N-(phenyl-C.sub.1-3-alk- yl)-amino or
N-(pyridyl-C.sub.1-3-alkyl)-amino group,
[0024] by an aminocarbonyl group which may be mono- or
disubstituted at the amino-nitrogen atom by a C.sub.1-3-alkyl
group,
[0025] by a pyrrolidinocarbonyl, piperidinocarbonyl,
morpholinocarbonyl or N-(C.sub.1-3-alkyl)-piperazinocarbonyl
group,
[0026] by a sulphonyl group substituted by an amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino, pyrrolidino,
piperidino, morpholino or N-(C.sub.1-3-alkyl)-piperazino group,
[0027] by an amino or N-(C.sub.1-3-alkyl)-amino group which is
substituted in each case at the amino-nitrogen atom by an
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl,
phenyl-C.sub.1-3-alkylaminocarbonyl, phenylaminocarbonyl,
pyridylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl,
morpholinocarbonyl or N-(C.sub.1-3-alkyl)-piperazinoc- arbonyl
group, whilst in the abovementioned aminocarbonyl groups any
hydrogen atom present may additionally be replaced by a
C.sub.1-3-alkyl group,
[0028] or by a 5 or 6-membered heteroaryl group,
[0029] whilst the abovementioned phenyl groups may additionally be
substituted by another fluorine, chlorine or bromine atom or by
another C.sub.1-3-alkyl or C.sub.1-3-alkoxy group and two
C.sub.1-.sub.3-alkoxy groups in the o position may be replaced by a
methylenedioxy group,
[0030] and the abovementioned 6-membered heteroaryl groups contain
one, two or three nitrogen atoms and the abovementioned 5-membered
heteroaryl groups contain an imino group optionally substituted by
a C.sub.1-3-alkyl group, an oxygen or sulphur atom, or an imino
group optionally substituted by a C.sub.1-3-alkyl group and an
oxygen or sulphur atom or one or two nitrogen atoms,
[0031] the isomers thereof and the salts thereof.
[0032] An essential feature of the invention is the fact that A
denotes a bicyclic heteroaryl group which is linked via the phenyl
ring to the R.sub.1 -substituted olefinic carbon atom.
[0033] By a group which can be converted in vivo into a carboxy
group is meant, for example, a hydroxmethyl group, a carboxy group
esterified with an alcohol, wherein the alcoholic moiety preferably
denotes a C.sub.1-6-alkanol, a phenyl-C.sub.1-3-alkanol, a
C.sub.3-9-cycloalkanol, whilst a C.sub.5-8-cycloalkanol may
additionally be substituted by one or two C.sub.1-3-alkyl groups, a
C.sub.5-8-cycloalkanol wherein a methylene group in the 3 or 4
position is replaced by an oxygen atom or by an imino group
optionally substituted by a C.sub.1-3-alkyl,
phenyl-C.sub.1-3-alkyl, phenyl-C.sub.1-3-alkoxycarbonyl or
C.sub.2-6-alkanoyl group and the cycloalkanol moiety may
additionally be substituted by one or two C.sub.1-3-alkyl groups, a
C.sub.4-7-cycloalkenol, a C.sub.3-5-alkenol, a
phenyl-C.sub.3-5-alkenol, a C.sub.3-5-alkynol or
phenyl-C.sub.3-5-alkynol, with the proviso that no bond to the
oxygen atom starts from a carbon atom which carries a double or
triple bond, a C.sub.3-8-cycloalkyl-C.sub.1-3-alkanol, a
bicycloalkanol having a total of 8 to 10 carbon atoms which may
additionally be substituted by one or two C.sub.1-3-alkyl groups in
the bicycloalkyl moiety, a 1,3-dihydro-3-oxo-1-isobenzfuranol or an
alcohol of formula
R.sub.a--CO--O--(R.sub.bCR.sub.c)--OH,
[0034] wherein
[0035] R.sub.a denotes a C.sub.1-8-alkyl, C.sub.5-7-cycloalkyl,
phenyl or phenyl- C.sub.1-3-alkyl group,
[0036] R.sub.b denotes a hydrogen atom, a C.sub.1-3-alkyl,
C.sub.5-7-cycloalkyl or phenyl group and R.sub.c denotes a hydrogen
atom or a C.sub.1-3-alkyl group,
[0037] by a group which is negatively charged under physiological
conditions is meant a carboxy, hydroxysulphonyl, phosphono,
tetrazol-5-yl, phenylcarbonylaminocarbonyl,
trifluoromethylcarbonylaminoc- arbonyl,
C.sub.1-6-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbon-
yl, benzylsulphonylaminocarbonyl or
perfluoro-C.sub.1-6-alkylsulphonylamin- ocarbonyl group.
[0038] Moreover, the saturated alkyl and alkoxy moieties containing
more than 2 carbon atoms mentioned in the definitions given above
and hereinafter also include the branched isomers thereof, such as
the isopropyl, tert.butyl, isobutyl group, etc.
[0039] Preferred compounds of the above general formula I are those
wherein
[0040] R.sub.1 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0041] R.sub.2 denotes a hydrogen, fluorine, chlorine or bromine
atom or a C.sub.1-3-alkyl group,
[0042] R.sub.3 denotes a hydrogen atom or a methyl group,
[0043] A denotes a chromane or chromene group linked via a fused-on
phenyl ring wherein a methylene group may be replaced by a carbonyl
group,
[0044] or a bicyclic heteroaryl group consisting of
[0045] a 5 or 6-membered heteroaryl group optionally substituted in
the carbon skeleton by a fluorine, chlorine or bromine atom, by a
C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, while the 6-membered
heteroaryl groups contain one, two or three nitrogen atoms and the
5-membered heteroaryl groups contain an imino group optionally
substituted by a C.sub.1-3-alkyl group, an oxygen or sulphur atom,
or an imino group optionally substituted by a C.sub.1-3-alkyl group
and an oxygen or sulphur atom or one or two nitrogen atoms,
[0046] and a phenyl ring fused to the abovementioned monocyclic
heteroaryl groups via two adjacent carbon atoms, by means of which
the bicyclic heteroaryl group is linked to the R.sub.1 -substituted
alkene-carbon atom and which may also be substituted in the carbon
skeleton by a fluorine, chlorine or bromine atom or by a methyl or
methoxy group,
[0047] and B denotes a 5 or 6-membered heteroaryl group substituted
by a carboxy group or by a group which may be converted into a
carboxy group in vivo
[0048] or a phenyl or naphthyl group which is substituted in each
case by a carboxy group or by a group which may be converted into a
carboxy group in vivo, while the abovementioned phenyl group is
additionally substituted
[0049] by a fluorine, chlorine or bromine atom,
[0050] by a C.sub.1-3-alkyl, trifluoromethyl, phenyl, hydroxy,
C13-alkoxy, carboxy, C.sub.1-3-alkoxycarbonyl, formyl,
C.sub.1-3-alkylcarbonyl, C.sub.1-3-alkylsulphonyl, phenylsulphonyl,
nitro, pyrrolidino, piperidino, morpholino,
N-(C.sub.1-3-alkyl)-piperazino, aminosulphonyl,
C.sub.1-3-alkylaminosulphonyl or
di-(C.sub.1-3-alkyl)-aminosulphonyl group,
[0051] by a n-C.sub.2-3-alkoxy group substituted in the 2 or 3
position by a di-(C.sub.1-3-alkyl)-amino group,
[0052] by an amino group, by an N-(C.sub.1-3-alkyl)-amino or
N,N-di-(C.sub.1-3-alkyl)-amino group wherein the alkyl moiety in
the 2 or 3 position relative to the nitrogen atom may be
substituted in each case by a C.sub.1-3-alkoxy group, by an
N-phenylamino, N-(phenyl-C.sub.1-3-alk- yl)-amino or
N-(pyridyl-C.sub.1-3-alkyl)-amino group,
[0053] by an aminocarbonyl group which may be mono or disubstituted
at the amino-nitrogen atom by a C.sub.1-3-alkyl group,
[0054] by a pyrrolidinocarbonyl, piperidinocarbonyl,
morpholinocarbonyl or N-(C.sub.1-3-alkyl)-piperazinocarbonyl group,
by a sulphonyl group substituted by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino- , pyrrolidino, piperidino, morpholino
or N-(C.sub.1-3-alkyl)-piperazino group,
[0055] or by an amino or N-(C.sub.1-3-alkyl)-amino group which is
substituted in each case at the amino-nitrogen atom by an
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl,
phenyl-C.sub.1-3-alkylaminocarbonyl, phenylaminocarbonyl,
pyridylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl,
morpholinocarbonyl or N-(C.sub.1-3-alkyl)-piperazinoc- arbonyl
group, wherein additionally any hydrogen atom present in one of the
abovementioned aminocarbonyl groups may be replaced by a
C.sub.1-3-alkyl group,
[0056] whilst the abovementioned phenyl groups may additionally be
substituted by another fluorine, chlorine or bromine atom or by
another C.sub.1-3-alkyl or C.sub.1-3-alkoxy group,
[0057] and the abovementioned 6-membered heteroaryl groups contain
one or two nitrogen atoms and the abovementioned 5-membered
heteroaryl groups contain an imino group optionally substituted by
a C.sub.1-3-alkyl group, an oxygen or sulphur atom, or an imino
group optionally substituted by a C.sub.1-3-alkyl group and an
oxygen or sulphur atom or one or two nitrogen atoms,
[0058] the isomers thereof and the salts thereof.
[0059] Particularly preferred new compounds of the above general
formula I are those wherein
[0060] B and R.sub.1 to R.sub.3 are as hereinbefore defined,
and
[0061] A denotes a chromane or chromene group linked via a fused-on
phenyl ring wherein a methylene group may be replaced by a carbonyl
group,
[0062] or a bicyclic heteroaryl group consisting of
[0063] a 5 or 6-membered heteroaryl group optionally substituted in
the carbon skeleton by a fluorine, chlorine or bromine atom, by a
methyl or methoxy group, while the 6-membered heteroaryl groups
contain one, two or three nitrogen atoms and the 5-membered
heteroaryl groups contain an imino group optionally substituted by
a methyl group, an oxygen or sulphur atom, or an imino group
optionally substituted by a methyl group and an oxygen or sulphur
atom or one or two nitrogen atoms,
[0064] and a phenyl ring fused to the abovementioned monocyclic
heteroaryl groups via two adjacent carbon atoms, by means of which
the bicyclic heteroaryl group is linked to the R.sub.1 substituted
alkene-carbon atom and which may also be substituted in the carbon
skeleton by a fluorine, chlorine or bromine atom or by a methyl or
methoxy group,
[0065] the isomers thereof and the salts thereof.
[0066] Most particularly preferred compounds of general formula I
are those wherein
[0067] R.sub.1 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0068] R.sub.2 denotes a hydrogen atom or a methyl group,
[0069] R.sub.3 denotes a hydrogen atom,
[0070] A denotes a benzofuryl, benzothienyl, quinolyl or
isoquinolyl group bound via the phenyl moiety to the R.sub.1
-substituted alkene-carbon atom and optionally substituted by a
methyl group and
[0071] B denotes a pyridyl, thienyl, pyrazolyl, quinolyl or
isoquinolyl group substituted by a carboxy group or
[0072] a phenyl group substituted by a carboxy, methoxycarbonyl or
ethoxycarbonyl group, which may additionally be substituted
[0073] by a fluorine, chlorine or bromine atom,
[0074] by a methyl, trifluoromethyl, phenyl, hydroxymethyl,
hydroxy, methoxy, 2-dimethylamino-ethoxy, nitro,
methylsulphonylamino, phenylsulphonylamino, aminosulphonyl,
pyrrolidino, piperidino or morpholino group,
[0075] by an amino, N-methyl-amino or N-(2-methoxy-ethyl)-amino
group which may be substituted in each case at the amino-nitrogen
atom by a C.sub.1-3-alkyl group,
[0076] or by an aminocarbonyl, methylaminocarbonyl or
dimethylaminocarbonyl group,
[0077] whilst the abovementioned phenyl groups may additionally be
substituted by another fluorine or chlorine atom or by another
methyl or methoxy group,
[0078] the isomers thereof and the salts thereof,
[0079] particularly those compounds of general formula I
wherein
[0080] R.sub.1 denotes a hydrogen atom, a methyl or ethyl
group,
[0081] R.sub.2 denotes a hydrogen atom,
[0082] R.sub.3 denotes a hydrogen atom,
[0083] A denotes a benzothienyl, quinolyl or isoquinolyl group
bound to the R.sub.1-substituted alkene-carbon atom via the phenyl
moiety and optionally substituted by a methyl group and
[0084] B denotes a phenyl, thienyl or pyridinyl group substituted
in each case by a carboxy group, while the abovementioned phenyl
group may additionally be substituted
[0085] by a fluorine, chlorine or bromine atom,
[0086] by a methyl, hydroxy, C.sub.1-3-alkoxy, pyrrolidino,
piperidino, morpholino or N-(C.sub.1-3-alkyl)-piperazino group,
[0087] by a 2-dimethylaminoethoxy group,
[0088] by an amino, methylamino or dimethylamino group or
[0089] by an aminocarbonyl, methylaminocarbonyl or
dimethylaminocarbonyl group and
[0090] the disubstituted phenyl groups may additionally be
substituted by another fluorine atom or by another methyl or
methoxy group,
[0091] the isomers thereof and the salts thereof.
[0092] Most preferred are compounds of general formula I
wherein
[0093] R.sub.1 denotes a methyl group,
[0094] R.sub.2 denotes a hydrogen atom,
[0095] R.sub.3 denotes a hydrogen atom,
[0096] A denotes a benzothienyl, quinolyl or isoquinolyl group
bound to the R.sub.1-substituted alkene-carbon atom via the phenyl
moiety and
[0097] B denotes a 2-carboxy-phenyl or 2-carboxy-thienyl group,
while the abovementioned 2-carboxy-phenyl group may additionally be
substituted in the phenyl nucleus
[0098] by a fluorine, chlorine or bromine atom,
[0099] by a methyl, hydroxy, C.sub.1-3-alkoxy, amino, methylamino,
dimethylamino or morpholino group,
[0100] by a 2-dimethylaminoethoxy group or
[0101] by an aminocarbonyl, methylaminocarbonyl or
dimethylaminocarbonyl group and optionally
[0102] additionally by another fluorine atom or by another methoxy
group,
[0103] the isomers thereof and the salts thereof.
[0104] The following are mentioned as examples of particularly
preferred compounds:
[0105] (1) trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-phenyl)- -amide,
[0106] (2) trans-3-(benzothien-5-yl)-but-2-enoic
acid-N-(2-carboxy-phenyl)- -amide,
[0107] (3) trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-4,5-dim- ethoxyphenyl)-amide,
[0108] (4) trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-6-methy- lphenyl)-amide,
[0109] (5) trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-4-fluor- ophenyl)-amide and
[0110] (6) trans-3-(quinolin-6-yl)-but-2-enoic
acid-N-(2-carboxy-phenyl)-a- mide,
[0111] as well as the salts thereof.
[0112] The carboxylic acid amides of the above general formula I
are obtained, for example, by the following methods known per
se:
[0113] a. Acylating an amine of general formula 3
[0114] wherein
[0115] R.sub.3 and B are as hereinbefore defined, with a carboxylic
acid of general formula 4
[0116] wherein
[0117] R.sub.1, R.sub.2 and A are as hereinbefore defined, or the
reactive derivatives thereof.
[0118] The acylation is conveniently carried out with a
corresponding halide or anhydride in a solvent such as methylene
chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran,
dioxane, benzene, chlorobenzene, toluene, acetonitrile or
sulpholane, optionally in the presence of an inorganic or organic
base such as triethylamine, N-ethyl-diisopropylamine,
N-methyl-morpholine or pyridine at temperatures between -20 and
200.degree. C., but preferably at temperatures between -10 and
160.degree. C.
[0119] However, the acylation may also be carried out with the free
acid, optionally in the presence of an acid-activating agent or a
dehydrating agent, e.g. in the presence of isobutyl chloroformate,
thionyl chloride, trimethylchlorosilane, hydrogen chloride,
sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid,
phosphorus trichloride, phosphorus pentoxide,
N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1
-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or
N,N'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride,
at temperatures between -20 and 200.degree. C., but preferably at
temperatures between -10 and 160.degree. C.
[0120] b. In order to prepare a carboxylic acid amide of general
formula I which contains a carboxy group:
[0121] converting a compound of general formula 5
[0122] wherein
[0123] R.sub.1 to R.sub.3, A and B are as hereinbefore defined,
with the proviso that B contains a group which can be converted
into a carboxy group, into a compound of general formula I which
contains a carboxy group.
[0124] Examples of a group which can be converted into a carboxy
group include carboxyl groups protected by protecting groups, such
as the functional derivatives thereof, e.g. the unsubstituted or
substituted amides, esters, thioesters, trimethylsilylesters,
orthoesters or iminoesters thereof, which are conveniently
converted into a carboxyl group by hydrolysis,
[0125] the esters thereof with tertiary alcohols, e.g. the tert.
butyl ester, which are conveniently converted into a carboxyl group
by treating with an acid or by thermolysis, and
[0126] the esters thereof with aralkanols, e.g. the benzyl ester,
which are conveniently converted into a carboxyl group by
hydrolysis.
[0127] The hydrolysis is conveniently carried out either in the
presence of an acid such as hydrochloric acid, sulphuric acid,
phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic
acid or mixtures thereof or in the presence of a base such as
lithium hydroxide, sodium hydroxide or potassium hydroxide in a
suitable solvent such as water, water/methanol, water/ethanol,
water/isopropanol, methanol, ethanol, water/tetrahydrofuran or
water/dioxane at temperatures between -10 and 120.degree. C., e.g.
at temperatures between ambient temperature and the boiling
temperature of the reaction mixture.
[0128] The conversion of a tert. butyl or tert. butyloxycarbonyl
group into a carboxy group can also be carried out by treating with
an acid such as trifluoroacetic acid, formic acid,
p-toluenesulphonic acid, sulphuric acid, hydrochloric acid,
phosphoric acid or polyphosphoric acid optionally in an inert
solvent such as methylene chloride, chloroform, benzene, toluene,
diethylether, tetrahydrofuran or dioxane, preferably at
temperatures between -10 and 120.degree. C., e.g. at temperatures
between 0 and 60.degree. C., or thermally, optionally in an inert
solvent such as methylene chloride, chloroform, benzene, toluene,
tetrahydrofuran or dioxane and preferably in the presence of a
catalytic amount of an acid such as p-toluenesulphonic acid,
sulphuric acid, phosphoric acid or polyphosphoric acid, preferably
at the boiling temperature of the solvent used, e.g. at
temperatures between 40 and 120.degree. C.
[0129] The conversion of a benzyloxy or benzyloxycarbonyl group
into a carboxy group may also be carried out hydrogenolytically in
the presence of a hydrogenation catalyst such as palladium/charcoal
in a suitable solvent such as methanol, ethanol, ethanol/water,
glacial acetic acid, ethyl acetate, dioxane or dimethylformamide,
preferably at temperatures between 0 and 50.degree. C., e.g. at
ambient temperature, and at a hydrogen pressure of 1 to 5 bar.
[0130] If according to the invention a compound of general formula
I is obtained which contains a hydroxy group, this may be converted
into a corresponding sulphonyloxy compound by means of a sulphonyl
halide, or
[0131] if a compound of general formula I is obtained which
contains a cyano group, this can be converted by means of hydrazoic
acid into a corresponding tetrazolyl compound, or
[0132] if a compound of general formula I is obtained which
contains an amino or imino group with a basic hydrogen atom, this
can be converted by acylation or sulphonylation into a
correspondingly acylated compound or into a corresponding prodrug
compound, or
[0133] if a compound of general formula I is obtained which
contains a carboxy group, this can be converted into a compound
which contains a group which may be converted into a carboxy group
in vivo, or
[0134] if a compound of general formula I is obtained which
contains one or two carboxy groups, this can be converted by
reduction with a complex metal hydride into a compound which
contains one or two hydroxymethyl groups.
[0135] The subsequent sulphonylation is conveniently carried out
with a corresponding halide in a solvent such as methylene
chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran,
dioxane, benzene, toluene, acetonitrile or sulpholane, optionally
in the presence of an inorganic or organic base such as
triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or
pyridine at temperatures between -20 and 200.degree. C., but
preferably at temperatures between -10 and 160.degree. C.
[0136] The subsequent preparation of a compound of general formula
I which contains a tetrazole group is preferably carried out in a
solvent such as benzene, toluene or dimethylformamide at
temperatures between 80 and 150.degree. C., preferably between 120
and 130.degree. C. The hydrazoic acid required is conveniently
liberated during the reaction from an alkali metal azide, e.g. from
sodium azide, in the presence of a weak acid such as ammonium
chloride. The reaction may also be carried out with another salt or
derivative of hydrazoic acid, preferably with aluminium azide or
tributyl tin azide, and the tetrazole compound optionally obtained
in this way is then liberated from the salt contained in the
reaction mixture by acidification with a dilute acid such as 2N
hydrochloric acid or 2N sulphuric acid.
[0137] The subsequent acylation or sulphonylation or the subsequent
conversion into a corresponding prodrug compound is preferably
carried out with a corresponding acid halide in a solvent such as
methylene chloride, chloroform, carbon tetrachloride, ether,
tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or
sulpholane, optionally in the presence of an inorganic or organic
base such as triethylamine, N-ethyl-diisopropylamine,
N-methyl-morpholine or pyridine at temperatures between -20 and
200.degree. C., but preferably at temperatures between -10 and
160.degree. C.
[0138] The subsequent conversion of a carboxy group into a group
which may be converted into a carboxy group in vivo is preferably
carried out by esterification with a corresponding alcohol or by
alkylation of the carboxy group. The esterification is conveniently
carried out in a solvent or mixture of solvents such as methylene
chloride, benzene, toluene, chlorobenzene, tetrahydrofuran,
benzene/tetrahydrofuran or dioxane, but preferably in an excess of
the alcohol used in the presence of a dehydrating agent, e.g. in
the presence of hydrochloric acid, sulphuric acid, isobutyl
chloroformate, thionyl chloride, trimethylchlorosilane,
hydrochloric acid, sulphuric acid, methanesulphonic acid,
p-toluenesulphonic acid, phosphorus trichloride, phosphorus
pentoxide, 2-(1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluroniu-
m-tetrafluoroborate, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,
N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole,
triphenylphosphine/carbon tetrachloride or
triphenylphosphine/diethyl azodicarboxylate, optionally in the
presence of a base such as potassium carbonate,
N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine,
conveniently at temperatures between 0 and 150.degree. C.,
preferably at temperatures between 0 and 80.degree. C., and the
alkylation is conveniently carried out with a corresponding halide
in a solvent such as methylene chloride, tetrahydrofuran, dioxane,
dimethylsulphoxide, dimethylformamide or acetone, optionally in the
presence of a reaction accelerator such as sodium or potassium
iodide and preferably in the presence of a base such as sodium
carbonate or potassium carbonate or in the presence of a tertiary
organic base such as N-ethyl-diisopropylamine or
N-methyl-morpholine, which may simultaneously serve as solvent, or
optionally in the presence of silver carbonate or silver oxide at
temperatures between -30 and 100.degree. C., but preferably at
temperatures between -10 and 80.degree. C.
[0139] The subsequent reduction is preferably carried out in the
presence of a complex metal hydride such as lithium aluminium
hydride or lithium triethyl borohydride in a solvent such as
tetrahydrofuran, conveniently at the boiling temperature of the
solvent used.
[0140] In the reactions described hereinbefore, any reactive groups
present such as hydroxy, carboxy, amino, alkylamino or imino groups
may be protected during the reaction by conventional protecting
groups which are cleaved again after the reaction.
[0141] For example, a protecting group for a hydroxy group may be a
trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl,
benzyl or tetrahydropyranyl group,
[0142] protecting groups for a carboxy group may be a
trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or
tetrahydropyranyl group and
[0143] protecting groups for an amino, alkylamino or imino group
may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,
tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or
2,4-dimethoxybenzyl group and additionally, for the amino group, a
phthalyl group.
[0144] Any protecting group used is optionally subsequently cleaved
for example by hydrolysis in an aqueous solvent, e.g. in water,
isopropanol/water, acetic acid/water, tetrahydrofuran/water or
dioxane/water, in the presence of an acid such as trifluoroacetic
acid, hydrochloric acid or sulphuric acid or in the presence of an
alkali metal base such as sodium hydroxide or potassium hydroxide
or aprotically, e.g. in the presence of iodotrimethylsilane, at
temperatures between 0 and 120.degree. C., preferably at
temperatures between 10 and 100.degree. C.
[0145] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group
is cleaved, for example hydrogenolytically, e.g. with hydrogen in
the presence of a catalyst such as palladium/charcoal in a suitable
solvent such as methanol, ethanol, ethyl acetate or glacial acetic
acid, optionally with the addition of an acid such as hydrochloric
acid at temperatures between 0 and 100.degree. C., but preferably
at temperatures between 20 and 60.degree. C., and at a hydrogen
pressure of 1 to 7 bar, but preferably 3 to 5 bar. A
2,4-dimethoxybenzyl group, however, is preferably cleaved in
trifluoroacetic acid in the presence of anisole.
[0146] A tert.butyl or tert.butyloxycarbonyl group is preferably
cleaved by treating with an acid such as trifluoroacetic acid or
hydrochloric acid or by treating with iodotrimethylsilane
optionally using a solvent such as methylene chloride, dioxane,
methanol or diethylether.
[0147] A trifluoroacetyl group is preferably cleaved by treating
with an acid such as hydrochloric acid, optionally in the presence
of a solvent such as acetic acid at temperatures between 50 and
120.degree. C. or by treating with sodium hydroxide solution
optionally in the presence of a solvent such as tetrahydrofuran at
temperatures between 0 and 50.degree. C.
[0148] A phthalyl group is preferably cleaved in the presence of
hydrazine or a primary amine such as methylamine, ethylamine or
n-butylamine in a solvent such as methanol, ethanol, isopropanol,
toluene/water or dioxane at temperatures between 20 and 50.degree.
C.
[0149] The compounds of general formulae 11 to IV used as starting
materials are known from the literature in some cases but may also
be prepared by methods known from the literature (cf. for example
Fulton et al. in J.Chem.Soc. 1939, page 200, S. Sano et al. in
Chem.Commun. 6, page 539 (1997) and D. H. Klaubert et al. in
J.Med.Chem. 24, 742-748 (1981)).
[0150] Moreover, the compounds of general formula I obtained may be
resolved into their enantiomers and/or diastereomers, as mentioned
hereinbefore. Thus, for example, compounds with at least one
optically active carbon atom may be separated into their
enantiomers.
[0151] Thus, for example, the compounds of general formula I
obtained which occur as racemates may be separated by methods known
per se (cf. Allinger N. L. and Eliel E. L. in "Topics in
Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their
optical enantiomers and compounds of general formula I with at
least 2 stereogenic centres may be resolved into their
diastereomers on the basis of their physical-chemical differences
using methods known per se, e.g. by chromatography and/or
fractional crystallisation, and, if these compounds are obtained in
racemic form, they may subsequently be resolved into the
enantiomers as mentioned above.
[0152] Furthermore, the compounds of formula I obtained may be
converted into the salts thereof, particularly for pharmaceutical
use into the physiologically acceptable salts with inorganic or
organic acids. Acids which may be used for this purpose include for
example hydrochloric acid, hydrobromic acid, sulphuric acid,
methanesulphonic acid, phosphoric acid, fumaric acid, succinic
acid, lactic acid, citric acid, tartaric acid or maleic acid.
[0153] Moreover, if the new compounds of formula I contain an
acidic group such as a carboxy group, they may subsequently, if
desired, be converted into the salts thereof with inorganic or
organic bases, particularly for pharmaceutical use into the
physiologically acceptable salts thereof. Suitable bases for this
purpose include for example sodium hydroxide, potassium hydroxide,
arginine, lysine, cyclohexylamine, ethanolamine, diethanolamine and
triethanolamine.
[0154] As already mentioned hereinbefore, the carboxylic acid
amides of general formula I and the salts thereof, particularly the
physiologically acceptable salts thereof, have an inhibiting effect
on telomerase.
[0155] The inhibiting effect of the carboxylic acid amides of
general formula I on telomerase was investigated as follows:
[0156] Materials and Methods:
[0157] 1.Preparation of nuclear extracts from HeLa cells: Nuclear
extracts were prepared according to Dignam (Dignam et al. in
Nucleic Acids Res. 11, 1475-1489 (1983)). All the steps were
carried out at 4.degree. C., all the equipment and solutions were
pre-cooled to 4.degree. C. At least 1.times.10.sup.9HeLa-S3 cells
growing in suspension culture (ATCC catalogue number CCL-2.2) were
harvested by centrifuging for 5 minutes at 1000.times. g and washed
once with PBS buffer (140 mM KCl; 2.7 mM KCl; 8.1 mM
Na.sub.2HPO.sub.4; 1.5 mM KH.sub.2PO.sub.4). After the cell volume
had been determined, the cells were suspended in 5 times the volume
of hypotonic buffer (10 mM HEPES/KOH, pH 7.8; 10 mM KCl; 1.5 mM
MgCl.sub.2) and then left for 10 minutes at 4.degree. C. After
centrifuging for 5 minutes at 1000.times. g the cell pellet was
suspended in twice the volume of hypotonic buffer in the presence
of 1 mM DTE and 1 mM PMSF and broken up with a Dounce homogeniser.
The homogenised material was made isotonic with 0.1 volume of
10-fold saline buffer (300 mM HEPES/KOH, pH 7.8; 1.4 M KCl; 30 mM
MgCl.sub.2). The cell nuclei were separated from the cytoplasmic
components by centrifuging and then suspended in twice the volume
of nuclear extraction buffer (20 mM HEPES/KOH, pH 7.9; 420 mM KCl;
1.5 mM MgCl.sub.2; 0.2 mM EDTA; 0.5 mM DTE; 25% glycerol). The
nuclei were broken up using a Dounce homogeniser and incubated for
30 minutes at 4.degree. C. with gentle stirring. Any insoluble
ingredients were removed by centrifuging for 30 minutes at 10,000
rpm (SS-34 Rotor). Then the nuclear extract was dialysed for 4-5
hours against AM-100 buffer (20 mM tris/HCl, pH 7.9; 100 mM KCl;
0.1 mM EDTA; 0.5 mM DTE; 20% glycerol). The nuclear extracts
obtained were frozen in liquid nitrogen and stored at -80.degree.
C.
[0158] 2. Telomerase test: The activity of telomerase in nuclear
extracts from HeLa cells was determined using the method described
by Morin (Morin in Cell 59, 521-529 (1989)). The nuclear extract
(up to 20 .mu.l per reaction) was incubated for 120 minutes at
30.degree. C. in a volume of 40 .mu.l in the presence of 25 mM
Tris/HCl pH 8.2, 1.25 mM dATP, 1.25 mM TTP, 6.35 .mu.M dGTP; 15
.mu.Ci .alpha.-.sup.32P-dGTP (3000 Ci/Mmol), 1 mM MgCl.sub.2, 1 mM
EGTA, 1.25 mM spermidine, 0.25 U RNasin, and 2.5 .mu.M of an
oligonucleotide primer (for example TEA-fw [CAT ACT GGC GAG CAG AGT
T], or TTA GGG TTA GGG TTA GGG) (=telomerase reaction). If the
inhibition constant of potential telomerase inhibitors was to be
determined, these were also added to the telomerase reaction in a
concentration range of from 1 nM to 100 .mu.M.
[0159] The reaction was then stopped by the addition of 50 .mu.l of
RNase stop buffer (10 mM tris/HCL, pH 8.0; 20 mM EDTA; 0.1 mg/ml of
RNase A 100 U/ml of RNase T1; 1000 cpm of an .alpha.-.sup.32P-dGTP
labelled, 430 bp DNA fragment) and incubation was continued for a
further 15 minutes at 37.degree. C. Proteins present in the
reaction mixture were cleaved by the addition of 50 .mu.l of
proteinase K buffer (10 mM tris/HCL, pH 8.0; 0.5% SDS; 0.3 mg/ml of
proteinase K) and subsequent incubation for 15 min at 37.degree. C.
The DNA was purified by extracting twice with phenol-chloroform and
precipitated by adding 2.4 M ammonium acetate; 3 .mu.g tRNA and
750,ul ethanol. Then the precipitated DNA was washed with 500 .mu.l
of 70% ethanol, dried at ambient temperature, taken up in 4 .mu.l
of formamide probe buffer (80% (v/v) formamide; 50 mM of
tris-borate, pH 8.3; 1 mM EDTA; 0.1 (w/v) of xylene cyanol; 0.1%
(w/v) bromophenol blue) and separated by electrophoresis on a
sequence gel (8% polyacrylamide, 7 M urea, 1.times. TBE buffer).
The DNA synthesised by telomerase in the presence or absence of
potential inhibitors was identified and quantified by
Phospho-Imager Analysis (Molecular Dynamics) and in this way the
concentration of inhibitor which inhibits the telomerase activity
by 50% (IC.sub.50) was determined. The radiolabelled DNA fragment
to which the RNase stop buffer had been added was used as an
internal control for the yield.
[0160] The inhibitors of Examples 1 to 6 inhibited the telomerase
activity by more than 50% at a concentration of 5 .mu.M.
[0161] The following abbreviations were used in the foregoing
description:
1 bp base pairs DNA deoxyribonucleic acid DTE 1,4-dithioerythritol
dATP deoxyadenosine triphosphate dGTP deoxyguanosine triphosphate
EDTA ethylenediamine-tetraacetic acid EGTA
ethyleneglycol-bis-(2-aminoethyl)-tetraacetic acid HEPES
4-(2-hydroxyethyl)-piperazine-1-ethanesulphonic acid PMSF
phenylmethanesulphonylfluoride RNase ribonuclease RNasin .RTM.
ribonuclease inhibitor (Promega GmbH, Mannheim) tRNA transfer
ribonucleic acid TTP thymidine triphosphate TRIS
tris-(hydroxymethyl)-aminomethane TBE TRIS-borate-EDTA rpm
revolutions per minute
[0162] In view of their biological properties, the carboxylic acid
amides of general formula I are suitable for treating
pathophysiological processes which are characterised by an
increased telomerase activity. These are e.g. tumour diseases such
as carcinomas, sarcomas and leukaemias including skin cancer (e.g.
plate epithelial carcinoma, basalioma, melanoma), small-cell
bronchial carcinoma, non-small-cell bronchial carcinoma, salivary
gland carcinoma, oesophageal carcinoma, laryngeal carcinoma,
pharyngeal carcinoma, thyroid carcinoma, gastric carcinoma,
colorectal carcinoma, pancreatic carcinoma, carcinoma of the liver,
carcinoma of the breast, uterine carcinoma, vaginal carcinoma,
ovarian carcinoma, prostate carcinoma, testicular carcinoma,
bladder carcinoma, renal carcinoma, Wilms' tumour, retinoblastoma,
astrocytoma, oligodendroglioma, meningioma, neuroblastoma, myeloma,
medulloblastoma, neurofibrosarcoma, thymoma, osteosarcoma,
chondrosarcoma, Ewing's sarcoma, fibrosarcoma, histiocytoma,
dermatofibrosarcoma, synovialoma, leiomyosarcoma, rhabdomyosarcoma,
liposarcoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, chronic
myeloid leukaemia, chronic lymphatic leukaemia, acute promyelocytic
leukaemia, acute lymphoblastoid leukaemia and acute myeloid
leukaemia.
[0163] In addition, the compounds may also be used to treat other
diseases which have an increased rate of cell division or increased
telomerase activity, such as e.g. epidermal hyperproliferation
(psoriasis), inflammatory processes (rheumatoid arthritis),
diseases of the immune system, etc.
[0164] The compounds are also useful for treating parasitic
diseases in man and animals, such as e.g. worm or fungal diseases
as well as diseases caused by protozoan pathogens, such as e.g.
Zooflagellata (Trypanosoma, Leishmania, Giardia), Rhizopoda
(Entamoeba spp.), Sporozoa (Plasmodium spp., Toxoplasma spp.),
Ciliata, etc.
[0165] For this purpose the carboxylic acid amides of general
formula I may optionally be used in conjunction with other
pharmacologically active compounds and therapeutic preparations
which will reduce tumour size, and incorporated in conventional
galenic preparations. These may be used, for example, in tumour
therapy, in monotherapy or in conjunction with irradiation,
surgical interventions or other anti-tumour therapeutics, e.g. in
conjunction with topoisomerase inhibitors (e.g. etoposide), mitosis
inhibitors (e.g. paclitaxel, vinblastine), cell cycle inhibitors
(e.g. flavopyridol), inhibitors of signal transduction (e.g.
farnesyltransferase inhibitors), compounds which interact with
nucleic acid (e.g. cis-platin, cyclophosphamide, adriamycin),
hormone antagonists (e.g. tamoxifen), inhibitors of metabolic
processes (e.g. 5-FU etc.), cytokines (e.g. interferons), tumour
vaccines, antibodies, etc. These combinations may be given either
simultaneously or sequentially.
[0166] The daily dose is 0.1 to 3 g by oral or intravenous route,
divided up into one to four doses a day. For this purpose the
compounds of general formula I, optionally in conjunction with the
other active substances mentioned above, may be formulated together
with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose,
magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric
acid, water, water/ethanol, water/glycerol, water/sorbitol,
water/polyethylene glycol, propylene glycol, cetylstearyl alcohol,
carboxymethylcellulose or fatty substances such as hard fat or
suitable mixtures thereof to produce conventional galenic
preparations such as plain or coated tablets, capsules, powders,
suspensions or suppositories.
[0167] The following Examples are intended to illustrate the
invention in more detail:
EXAMPLE 1
[0168] trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxyphenyl)-amid- e
[0169] 1a) ethyl trans-3-(benzothien-6-yl)-but-2-enoate
[0170] 3.81 g (17.0 mmol) of diethyl ethoxycarbonylmethane
phosphonate were combined with 1.91 g (17.0 mmol) of potassium
tert. butoxide in 60 ml dimethylformamide and stirred for 20
minutes at ambient temperature. Then 3.00 g (17 mmol) of
(benzothien-6-yl)-ethanone (for synthesis see S. L. Graham et al.,
J. Med. Chem. 32 (12), p.2548-54 (1989)) were added and stirring
was continued for another 17 hours at ambient temperature. The
reaction mixture was then stirred into about 100 ml of ice water,
about 5 g of sodium chloride were added and the mixture was
extracted three times with 40 ml ethyl acetate. Chromatographic
purification of the crude product thus obtained using 200 g of
silica gel (petroleum ether +5% ethyl acetate) yielded 3.01 g (71 %
of theory) of ethyl trans-3-(benzothien-6-yl)-but-2-enoate.
[0171] C.sub.14H.sub.14O.sub.2S (246.3)
[0172] R.sub.f value: 0.55 (silica gel, petroleum ether/ethyl
acetate 4:1)
[0173] 1b) trans-3-(benzothien-6-yl)-but-2-enoic acid
[0174] 3.00 g (12.2 mmol) of ethyl
trans-3-(benzothien-6-yl)-but-2-enoate were stirred in 70 ml of
ethanol and 25 ml of 2N sodium hydroxide solution for two hours at
50.degree. C. The alcohol was then evaporated off in vacuo and the
solution was acidified with hydrochloric acid. The crude product
thus precipitated was chromatographed over 200 g of silica gel
(dichloromethane +1-4% ethanol).
[0175] C.sub.12H.sub.10O.sub.2S (218.3)
[0176] Yield: 2.03 g (75% of theory)
[0177] R.sub.f value: 0.22 (silica gel, dichloromethane/ethanol
50:1)
[0178] 1c) trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-methoxycarbonyl- -phenyl)-amide
[0179] 420 mg (1.92 mmol) of trans-3-(benzothien-6-yl)-but-2-enoic
acid were stirred in 2 ml of thionyl chloride after the addition of
0.01 ml of dimethylformamide for 30 minutes at ambient temperature
and then evaporated to dryness in vacuo. The acid chloride thus
obtained was refluxed in crude form together with 287 mg (1.90
mmol) of methyl anthranilate in 30 ml of toluene for four hours.
The mixture was then evaporated to dryness in vacuo and the residue
was chromatographed over 100 g of silica gel (petroleum ether/ethyl
acetate 7:3).
[0180] C.sub.20H.sub.17NO.sub.3S (351.4)
[0181] Yield: 480 mg (71% of theory)
[0182] R.sub.f value: 0.62 (silica gel, petroleum ether/ethyl
acetate 4:1)
[0183] Mass spectrum: (M+Na).sup.+=374 (M-H).sup.-=350
[0184] 1d) trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxyphenyl)-- amide
[0185] 480 mg (1.37 mmol) of trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-methoxycarbonyl-phenyl)-amide were stirred in 30 ml of
methanol and 2 ml of 2N sodium hydroxide solution for two hours at
ambient temperature, then the alcohol was evaporated off in vacuo,
the residue was diluted with about 30 ml of water and acidified
with hydrochloric acid. The product precipitated was suction
filtered, washed with water and dried.
[0186] C.sub.19H.sub.15NO.sub.3S (337.4)
[0187] Yield: 400.0 mg (87% of theory)
[0188] R.sub.f value: 0.22 (silica gel, dichloromethane/ethanol
50:1)
[0189] Mass spectrum: (M+Na).sup.+=360 (M-H).sup.-=336
(M+2Na--H).sup.+=382
EXAMPLE 2
[0190] trans-3-(benzothien-5-yl)-but-2-enoic
acid-N-(2-carboxyphenyl)-amid- e
[0191] 2a) ethyl trans-3-(benzothien-5-yl)-but-2-enoate
[0192] Prepared analogously to Example 1 a from
(benzothien-5-yl)-ethanone (for synthesis see S. Datta et al., J.
Chem. Soc. Perkin Trans. 1, 1989, p. 603-7).
[0193] C.sub.14H.sub.14O.sub.2S (246.3)
[0194] Yield: 2.70 g (41% of theory)
[0195] R.sub.f value: 0.72 (silica gel, petroleum ether/ethyl
acetate 4:1)
[0196] Mass spectrum: (M+Na).sup.+=269
[0197] 2b) trans-3-(benzothien-5-yl)-but-2-enoic acid
[0198] Prepared analogously to Example 1 b from
trans-3-(benzothien-5-yl)-- but-2-enoate ethyl and methanolic
sodium hydroxide solution.
[0199] C.sub.12H.sub.10O.sub.2S (218.3)
[0200] Yield: 2.20 g (92% of theory)
[0201] R.sub.f value: 0.48 (silica gel, dichloromethane/ethanol
9:1)
[0202] 2c) trans-3-(benzothien-5-yl)-but-2-enoic
acid-N-(2-methoxycarbonyl- -phenyl)-amide
[0203] Prepared analogously to Example 1c from 1.08 g (4.56 mmol)
of trans-3-(benzothien-5-yl)-but-2-enoic acid and methyl
anthranilate.
[0204] C.sub.20H.sub.17NO.sub.3S (351.4)
[0205] Yield: 1.10 g (69% of theory)
[0206] R.sub.f value: 0.62 (silica gel, petroleum ether/ethyl
acetate 4:1)
[0207] Mass spectrum: (M+Na).sup.+=374 (M+H).sup.+=352
(M-H).sup.-=350
[0208] 2d) trans-3-(benzothien-5-yl)-but-2-enoic
acid-N-(2-carboxyphenyl)-- amide
[0209] Prepared analogously to Example 1d from 1.10 g (3.13 mmol)
of trans-3-(benzothien-5-yl)-but-2-enoic
acid-N-(2-methoxycarbonyl-phenyl)-a- mide and methanolic sodium
hydroxide solution.
[0210] C.sub.19H.sub.15NO.sub.3S (337.4)
[0211] Yield: 350 mg (33% of theory)
[0212] R.sub.f value: 0.30 (silica gel, dichloromethane/ethanol
19:1)
[0213] Mass spectrum: (M+Na).sup.+=360 (M-H).sup.-=336
(M+2Na-H).sup.+=382
EXAMPLE 3
[0214] trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-4,5-dimetho- xy-phenyl)-amide
[0215] Prepared analogously to Example 1 from
trans-3-(benzothien-6-yl)-bu- t-2-enoic
acid-N-(4,5-dimethoxy-2-methoxycarbony-phenyl)-amide and methanolic
sodium hydroxide solution.
[0216] C.sub.21H.sub.19NO.sub.5S (397.5)
[0217] Yield: 79% of theory
[0218] R.sub.f value: 0.39 (silica gel, dichloromethane/ethanol
19:1)
[0219] Mass spectrum: (M+Na).sup.+=420 (M-H).sup.-=396
(M+2Na-H).sup.+=442
EXAMPLE 4
[0220] trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-6-methyl-ph- enyl)-amide
[0221] Prepared analogously to Example 1 from
trans-3-(benzothien-6-yl)-bu- t-2-enoic
acid-N-(6-methyl-2-methoxycarbony-phenyl)-amide and methanolic
sodium hydroxide solution.
[0222] C.sub.20H.sub.17NO.sub.3S (351.4)
[0223] Yield: 47% of theory
[0224] R.sub.f value: 0.28 (silica gel, dichloromethane/ethanol
19:1)
[0225] Mass spectrum: (M+Na).sup.+=374 (M-H).sup.-=350
(M+2Na-H).sup.+=396
EXAMPLE 5
[0226] trans-3-(benzothien-6-yl)-but-2-enoic
acid-N-(2-carboxy-4-fluorophe- nyl)-amide
[0227] Prepared analogously to Example 1 from
trans-3-(benzothien-6-yl)-bu- t-2-enoic
acid-N-(4-fluoro-2-methoxycarbony-phenyl)-amide and methanolic
sodium hydroxide solution.
[0228] C.sub.19H.sub.4FNO.sub.3S (355.4)
[0229] Yield: 62% of theory
[0230] R.sub.f value: 0.26 (silica gel, dichloromethane/ethanol
19:1)
[0231] Mass spectrum: (M-H).sup.-=354 (M+2Na-H).sup.+=400
EXAMPLE 6
[0232] trans-3-(quinolin-6-yl)-but-2-enoic
acid-N-(2-carboxy-phenyl)-amide
[0233] 6a) ethyl trans-3-(quinolin-6-yl)-but-2-enoate
[0234] Prepared analogously to Example 1a from 1.71 g (10.0 mmol)
of (quinolin-6-yl)-ethanone (for synthesis see: Lugowkin, Zh.
Obshch. Khim. 25 English edition p.371 (1955)).
[0235] C.sub.15H.sub.15NO.sub.2 (241.3)
[0236] Yield: 1.80 g (75% of theory)
[0237] R.sub.f value: 0.41 (silica gel, petroleum ether/ethyl
acetate 2:1)
[0238] Mass spectrum: (M+Na).sup.+=264
[0239] 6b) trans-3-(quinolin-6-yl)-but-2-enoic acid Prepared
analogously to Example 1 b from 1.80 g (7.46 mmol) of ethyl
trans-3-(quinolin-6-yl)-b- ut-2-enoate and methanolic sodium
hydroxide solution.
[0240] C.sub.13H.sub.11NO.sub.2 (213.2)
[0241] Yield: 0.80 g (50% of theory)
[0242] R.sub.f value: 0.21 (silica gel, dichloromethane/ethanol
19:1)
[0243] Mass spectrum: (M+H).sup.+=214 (M-H).sup.-=212
[0244] 6c) trans-3-(quinolin-6-yl)-but-2-enoic
acid-N-(2-methoxycarbonyl-P- henyl)-amide
[0245] Prepared analogously to Example 1c from 0.27 g (1.17 mmol)
of trans-3-(quinolin-6-yl)-but-2-enoic acid and methyl
anthranilate.
[0246] C.sub.21H.sub.18N.sub.2O.sub.3 (346.4)
[0247] Yield: 0.34 g (84% of theory)
[0248] R.sub.f value: 0.54 (silica gel, petroleum ether/ethyl
acetate 4:1)
[0249] Mass spectrum: (M+Na).sup.+=369 (M+H).sup.+=347
(M-H).sup.-=345
[0250] 6d) trans-3-(quinolin-6-yl)-but-2-enoic
acid-N-(2-carboxyphenyl)-am- ide
[0251] Prepared analogously to Example 1d from 340 mg (0.98 mmol)
of trans-3-(quinolin-6-yl)-but-2-enoic
acid-N-(2-methoxycarbonyl-phenyl)-ami- de and methanolic sodium
hydroxide solution.
[0252] C.sub.20H.sub.16N.sub.2O.sub.3 (332.4)
[0253] Yield: 300 mg (92% of theory)
[0254] R.sub.f value: 0.27 (silica gel, dichloromethane/ethanol
19:1)
[0255] Mass spectrum: (M+2Na-H).sup.+=377 (M-H).sup.-=331
EXAMPLE 7
[0256] Tablets Containing 50 mg of Active Substance
2 Active substance 50.0 mg Calcium phosphate 70.0 mg Lactose 40.0
mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium
stearate 1.5 mg 200.0 mg
[0257] Preparation:
[0258] The active substance, CaHPO.sub.4, lactose and corn starch
are evenly moistened with an aqueous PVP solution. The mass is
passed through a 2-mm screen, dried in a circulating air drier at
50.degree. C. and screened again.
[0259] After the lubricant has been mixed in, the granules are
compressed in a tablet-making machine.
EXAMPLE 8
[0260] Coated Tablets Containing 50 mg of Active Substance
3 Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn
starch 34.0 mg Gelatine 10.0 mg Magnesium stearate 1.0 mg 180.0
mg
[0261] Preparation:
[0262] The active substance is mixed with the excipients and
moistened with an aqueous gelatine solution. After screening and
drying, the granules are mixed with magnesium stearate and
compressed to form tablet cores.
[0263] The cores thus produced are covered with a coating by known
methods. The coating suspension or solution may have colouring
added to it.
EXAMPLE 9
[0264] Coated Tablets Containing 100 mg of Active Substance
4 Active substance 100.0 mg Lysine 50.0 mg Lactose 86.0 mg Corn
starch 50.0 mg Polyvinylpyrrolidone 2.8 mg Microcrystalline
cellulose 60.0 mg Magnesium stearate 1.2 mg 350.0 mg
[0265] Preparation:
[0266] The active substance is mixed with the excipients and
moistened with an aqueous PVP solution. The moist mass is passed
through a 1.5 mm screen and dried at 45.degree. C. After drying,
the mass is screened again and the magnesium stearate is added.
This mixture is compressed to form tablet cores.
[0267] The cores thus produced are covered with a coating by known
methods. The coating suspension or solution may have colouring
added to it.
EXAMPLE 10
[0268] Capsules Containing 250 mg of Active Substance
5 Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate
1.5 mg 320.0 mg
[0269] Preparation:
[0270] Active substance and corn starch are mixed together and
moistened with water. The moist mass is screened and dried. The dry
granules are screened and mixed with magnesium stearate. The final
mixture is packed into size 1 hard gelatine capsules.
* * * * *